Biomedical subjects

Ronald W Oppenheim

Publications and source records attributed to Ronald W Oppenheim.

At least 19 recordsLinked to original sources

PubMed2006

Neuromuscular development in the absence of programmed cell death: phenotypic alteration of motoneurons and muscle.

The widespread, massive loss of developing neurons in the central and peripheral nervous system of birds and mammals is generally considered to be an evolutionary adaptation. However, until recently, models for testing both the immediate and long-term consequences of preventing this normal cell loss have not been available. We have taken advantage of several methods for preventing neuronal death in vivo to ask whether rescued neurons [e.g., motoneurons (MNs)] differentiate normally and become functionally incorporated into the nervous system. Although many aspects of MN differentiation occurred normally after the prevention of cell death (including the expression of several motoneuron-specific markers, axon projections into the ventral root and peripheral nerves, ultrastructure, dendritic arborization, and afferent axosomatic synapses), other features of the neuromuscular system (MNs and muscle) were abnormal. The cell bodies and axons of MNs were smaller than normal, many MN axons failed to become myelinated or to form functional synaptic contacts with target muscles, and a subpopulation of rescued cells were transformed from alpha- to gamma-like MNs. Additionally, after the rescue of MNs in myogenin glial cell line-derived neurotrophic factor (MyoGDNF) transgenic mice, myofiber differentiation of extrafusal skeletal muscle was transformed and muscle physiology and motor behaviors were abnormal. In contrast, extrafusal myofiber phenotype, muscle physiology, and (except for muscle strength tests) motor behaviors were all normal after the rescue of MNs by genetic deletion of the proapoptotic gene Bax. However, there was an increase in intrafusal muscle fibers (spindles) in Bax knock-out versus both wild-type and MyoGDNF mice. Together, these data indicate that after the prevention of MN death, the neuromuscular system becomes transformed in novel ways to compensate for the presence of the thousands of excess cells.

Animals↗

PubMed2006

An in vivo analysis of Schwann cell programmed cell death in embryonic mice: the role of axons, glial growth factor, and the pro-apoptotic gene Bax.

Building upon previous in vitro studies, the present investigation involves an in vivo examination of Schwann cell programmed cell death (PCD) and development in the brachial spinal ventral roots of embryonic mice. The period of Schwann cell PCD was found to occur between embryonic days (E) 11.5 and 18.5, which is in close coincidence with the PCD period of associated brachial motoneurons (E13.5-E18.5). Additionally, Schwann cells exhibited a peak in proliferation at E11.5, and differentiation from the precursor to the immature Schwann cell stage between E12.5 and E14.5. Axon-mediated Schwann cell survival was demonstrated in vivo by excitotoxic elimination of motoneurons and their axons, via NMDA treatment in utero. This treatment increased apoptotic Schwann cell death within degenerating ventral roots. Conversely, in utero co-treatment of glial growth factor (GGF) with NMDA resulted in decreased Schwann cell death, a finding which supports previous reports of the promotion of Schwann cell survival by GGF. Analysis of mice lacking Bax, a pro-apoptotic Bcl-2 protein, revealed that Schwann cell PCD occurred independently of Bax. However, owing to the lack of motoneuron PCD in Bax-knockout mice, and the corresponding increase in the number of ventral root axons, a decrease in Schwann cell PCD was observed during the normal period of motoneuron PCD. In conclusion, our findings regarding the regulation of Schwann cell development in vivo are consistent with the conclusions from in vitro studies, including a dependency on axons for survival and proliferation signals, timing of differentiation, and a dependency on GGF.

Animals↗

PubMed2006

Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS.

The death of cranial and spinal motoneurons (MNs) is believed to be an essential component of the pathogenesis of amyotrophic lateral sclerosis (ALS). We tested this hypothesis by crossing Bax-deficient mice with mice expressing mutant superoxide dismutase 1 (SOD1), a transgenic model of familial ALS. Although Bax deletion failed to prevent neuromuscular denervation and mitochondrial vacuolization, MNs were completely rescued from mutant SOD1-mediated death. However, Bax deficiency extended lifespan and delayed the onset of motor dysfunction of SOD1 mutants, suggesting that Bax acts via a mechanism distinct from cell death activation. Consistent with this idea, Bax elimination delayed the onset of neuromuscular denervation, which began long before the activation of cell death proteins in SOD1 mutants. Additionally, we show that denervation preceded accumulation of mutant SOD1 within MNs and astrogliosis in the spinal cord, which are also both delayed in Bax-deficient SOD1 mutants. Interestingly, MNs exhibited mitochondrial abnormalities at the innervated neuromuscular junction at the onset of neuromuscular denervation. Additionally, both MN presynaptic terminals and terminal Schwann cells expressed high levels of mutant SOD1 before MNs withdrew their axons. Together, these data support the idea that clinical symptoms in the SOD1 G93A model of ALS result specifically from damage to the distal motor axon and not from activation of the death pathway, and cast doubt on the utility of anti-apoptotic therapies to combat ALS. Furthermore, they suggest a novel, cell death-independent role for Bax in facilitating mutant SOD1-mediated motor denervation.

Amyotrophic Lateral Sclerosis↗

PubMed2006

Adaptive roles of programmed cell death during nervous system development.

The programmed cell death (PCD) of developing cells is considered an essential adaptive process that evolved to serve diverse roles. We review the putative adaptive functions of PCD in the animal kingdom with a major focus on PCD in the developing nervous system. Considerable evidence is consistent with the role of PCD in events ranging from neurulation and synaptogenesis to the elimination of adult-generated CNS cells. The remarkable recent progress in our understanding of the genetic regulation of PCD has made it possible to perturb (inhibit) PCD and determine the possible repercussions for nervous system development and function. Although still in their infancy, these studies have so far revealed few striking behavioral or functional phenotypes.

Adaptation, Physiological↗

PubMed2005

Phosphorylation of c-Jun in avian and mammalian motoneurons in vivo during programmed cell death: an early reversible event in the apoptotic cascade.

c-Jun is a transcription factor that is involved in various cellular events, including apoptotic cell death. For example, phosphorylation of c-Jun is one of the earliest biochemical changes detected in dying sympathetic neurons after NGF deprivation in vitro. However, currently, it is not known whether a similar molecular event is involved in the developmental programmed cell death (PCD) of neurons in vivo. We observed that only a subpopulation of motoneurons (MNs) exhibit c-Jun phosphorylation during the PCD period in chick [embryonic day 5 (E5)-E12] and mouse (E13-E18) embryos. Experimental perturbation of MN survival-promoting signals by limb bud removal (reduced signals) or by activity blockade (increased signals) in the chick embryo demonstrated that the presence of those signals is negatively correlated with the number of c-Jun-phosphorylated MNs. This suggests that insufficient survival signals (e.g., neurotrophic factors) may induce c-Jun phosphorylation of MNs in vivo. Consistent with the idea that c-Jun phosphorylation is a reversible event during normal PCD of MNs, we found that c-Jun phosphorylation was transiently observed in a subpopulation of mouse MNs rescued from PCD by deletion of the proapoptotic gene Bax. Inhibition of c-Jun signaling significantly reduced MN death in chick embryo, indicating that activation of c-Jun signaling is necessary for the PCD of MNs. Together, c-Jun phosphorylation appears to be required for the initiation of an early and reversible event in the intracellular PCD cascade in vivo after loss of survival-promoting signals such as neurotrophic factors.

Animals↗

PubMed2005

Protein retention in the endoplasmic reticulum, blockade of programmed cell death and autophagy selectively occur in spinal cord motoneurons after glutamate receptor-mediated injury.

We previously showed that, in contrast to the acute administration of NMDA, chronic treatment of chick embryos from embryonic day (E) 5 to E9 with this excitotoxin rescues motoneurons (MNs) from programmed cell death. Following this protocol, MNs are also protected against later acute excitotoxic cell death. Previously, we found that MNs treated from E5 to E9 develop long-lasting changes involving vesicular trafficking and other organelle pathology similar to the abnormalities observed in certain chronic neurological diseases including amyotrophic lateral sclerosis (ALS). Here we extend these previous results by showing that protein aggregation within the endoplasmic reticulum (ER) takes place selectively in MNs as an early event of chronic excitotoxicity. Although protein aggregates do not induce appreciable MN death, they foreshadow the activation of a conspicuous autophagic response leading to long-lasting degenerative changes that causes dysfunction but not immediate cell death. Chronic early treatment with NMDA results in a transient (between E6 and E10) lack of vulnerability to undergo cell death induced by different types of stimuli. It is suggested that blockade of protein translation in stressed ER may inhibit apoptosis in NMDA-treated MNs. However, in embryos older than E12, degenerating MNs are sensitized to die after limb ablation (axotomy) and accumulate hyperphosphorylated neurofilaments. Moreover, chronic NMDA treatment does not induce the upregulation of molecular chaperones in spinal cord. These results represent a new model of glutamate receptor-mediated neurotoxicity that selectively occurs in spinal cord MNs and also demonstrate an experimental system that may be valuable for understanding the mechanisms involved in chronic MN degeneration and in certain cytological hallmarks of ALS-diseased MNs such as inclusion bodies.

Amyotrophic Lateral Sclerosis↗

PubMed2004

Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax.

In the dentate gyrus (DG) of the adult mouse hippocampus, a substantial number of new cells are generated daily, but only a subset of these survive and differentiate into mature neurons, whereas the majority undergo programmed cell death (PCD). However, neither the intracellular machinery required for adult stem cell-derived neuronal death nor the biological implications of the significant loss of these newly generated cells have been examined. Several markers for apoptosis failed to reveal cell death in Bax-deficient mice, and this, together with a progressive increase in neuron number in the DG of the Bax knock-out, indicates that Bax is critical for the PCD of adult-generated hippocampal neurons. Whereas the proliferation of neural progenitor cells was not altered in the Bax-knock-out, there was an accumulation of doublecortin, calretinin+, and neuronal-specific nuclear protein+ postmitotic neurons, suggesting that Bax-mediated PCD of adult-generated neurons takes place during an early phase of differentiation. The absence of PCD in the adult also influenced the migration and maturation of adult-generated DG neurons. These results suggest that PCD in the adult brain plays a significant role in the regulation of multiple aspects of adult neurogenesis.

Aging↗

PubMed2004

The function of neurotrophic factor receptors expressed by the developing adductor motor pool in vivo.

We examined the spatio-temporal relationship between neurotrophic factor receptor (NTF-R) expression and motoneuron (MN) survival in the developing avian spinal cord and observed heterogeneity in the expression of NTF-Rs between, but not within, pools of MNs projecting to individual muscles. We then focused on the role of NTFs in regulating the survival of one motor pool of MNs, all of which innervate a pair of adductor muscles in the thigh and hence compete for survival during the period of programmed cell death (PCD). The complete NTF-R complement of these MNs was analyzed and found to include many, but not all, NTF-Rs. Treatment with exogenous individual NTFs rescued some, but not all, adductor MNs expressing appropriate NTF-Rs. In contrast, administration of multiple NTFs completely rescued adductor MNs from PCD. Additionally, adductor MNs were partially rescued from PCD by NTFs for which they failed to express receptors. NTF-Rs expressed by the nerve but not in the muscle target were capable of mediating survival signals to MNs in trans. Finally, the expression of some NTF-Rs by adductor MNs was not required for MN survival. These studies demonstrate the complexity in NTF regulation of a defined subset of competing MNs and suggest that properties other than NTF-R expression itself can play a role in mediating trophic responses to NTFs.

Animals↗

PubMed2004

Distinct muscle targets do not vary in the developmental regulation of brain-derived neurotrophic factor. J Comp Neurol 470:317-329,2004.

Developing neurons depend on many target-derived signals. One of these signals is the neurotrophin brain-derived neurotrophic factor (BDNF). Exogenous application of BDNF in vitro and in vivo rescues a population of lumbar motoneurons from programmed cell death. Given that BDNF does not rescue all motoneurons and that motoneurons differ in trophic factor receptor expression, subpopulations of motoneurons may have different sensitivities to the factor. These differences may be reflected in distinct target muscles specialized to produce different protein concentrations, or muscles may contain equal amounts of the factor and receptor expression determines motoneuron responsiveness. By using a sensitive electrochemiluminescent immunoassay (ECLIA), we measured normal developmental changes in BDNF protein concentration in anatomically and functionally distinct chick embryonic thigh muscles from E6 to E18. We found that there were no significant differences in BDNF protein concentration between muscles classified according to function (fast vs. slow) or anatomical position (flexor vs. extensor) and that the quantity of BDNF in the target did not appear to be activity dependent. These results suggest that, during development, the differences in the response of motoneurons to BDNF are not due to the anatomical or functional diversity of muscle targets. J. Comp. Neurol. 470:330-337, 2004.

Animals↗

PubMed2004

The kiss of death.

The programmed cell death (PCD) of neurons is generally thought to be cell autonomous and not to require a death signal from other cells. A recent study by Marín-Teva et al., in this issue of Neuron, brings this theory into question and suggests that neighboring microglia actively participate in the PCD of Purkinje cells in the cerebellum.

Animals↗

PubMed2004

Overexpression of glial cell line-derived neurotrophic factor in the CNS rescues motoneurons from programmed cell death and promotes their long-term survival following axotomy.

To study the role of one of the most potent motoneuron (MN) survival factors, glial cell line-derived neurotrophic factor (GDNF) derived from the CNS, we generated transgenic animals overexpressing GDNF under the control of an astrocyte-specific GFAP promoter. In situ hybridization revealed that GDNF was expressed at high levels in astrocytes throughout the brain and spinal cord. We analyzed the effects of CNS-derived GDNF on MN survival during the period of programmed cell death (PCD) and after nerve axotomy. In GFAP-GDNF mice at E15, E18, and P1, the survival of brachial MNs was increased on average by 30%, lumbar MNs by 20%, and thoracic MNs at P1 by 33%. GDNF also prevented MN PCD in several cranial motor nuclei. We demonstrated for the first time that the number of MNs in the mouse abducens nucleus was also increased by 40%, thus extending known MN populations that are responsive to GDNF. Next, we tested if GDNF could support complete and relatively long-term survival of MNs following neonatal facial nerve axotomy. We found that virtually all MNs (91%) in GFAP-GDNF mice survived for up to 18 weeks post-axotomy. This is the longest GDNF-mediated survival of neonatal MNs reported following axotomy. Most of surviving MNs were not atrophic, and MN-specific ChAT and neurofilament immunoreactivity (IR) were preserved. Furthermore, GDNF attenuated axotomy-induced astroglial activation. These data demonstrate that overexpression of GDNF in the CNS has very profound effects on MN survival both during the PCD period and after neuronal injury. GFAP-GDNF mice will be valuable to study the effects of CNS-derived GDNF in mouse models of MN degenerative diseases and axonal regeneration in vivo.

Animals↗

PubMed2004

Role of programmed cell death in normal neuronal development and function.

The consequences of eliminating the process of programmed cell death during the development of the nervous system is examined by reviewing studies in the genetic model organisms Caenorhabditis elegans, Drosophila melanogaster, Danio rerio and Mus musculus, where mutations of cell death genes have eliminated or reduced programmed cell death in the nervous system. In many cases, genetic elimination of cell death leads to embryonic mortality or gross anatomical malformations; however, there are cases where animals develop normally but with excess neurons and glia in the nervous system. Undead cells either differentiate and function as working neurons, in some instances being of smaller size, or fail to differentiate and lack normal connections with their targets. Changes in motor control and sensory processing are generally not observed, except for during the most complex of behaviors. Examination of organisms where death genes have been genetically eliminated reveals that programmed cell death may play an important role in sculpting gross brain structure during early development of the neural tube. In contrast, the consequences of preventing neuronal cell death at later developmental stages (e.g. during vertebrate synapse formation) are just beginning to be understood.

Animals↗

PubMed2003

Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo.

The ciliary neurotrophic factor alpha-receptor (CNTFRalpha) is required for motoneuron survival during development, but the relevant ligand(s) has not been determined. One candidate is the heterodimer formed by cardiotrophin-like cytokine (CLC) and cytokine-like factor 1 (CLF). CLC/CLF binds to CNTFRalpha and enhances the survival of developing motoneurons in vitro; whether this novel trophic factor plays a role in neural development in vivo has not been tested. We examined motor and sensory neurons in embryonic chicks treated with CLC and in mice with a targeted deletion of the clf gene. Treatment with CLC increased the number of lumbar spinal cord motoneurons that survived the cell death period in chicks. However, this effect was regionally specific, because brachial and thoracic motoneurons were unaffected. Similarly, newborn clf-/- mice exhibited a significant reduction in lumbar motoneurons, with no change in the brachial or thoracic cord. Clf deletion also affected brainstem motor nuclei in a regionally specific manner; the number of motoneurons in the facial but not hypoglossal nucleus was significantly reduced. Sensory neurons of the dorsal root ganglia were not affected by either CLC treatment or clf gene deletion. Finally, mRNA for both clc and clf was found in skeletal muscle fibers of embryonic mice during the motoneuron cell death period. These findings support the view that CLC/CLF is a target-derived factor required for the survival of specific pools of motoneurons. The in vivo actions of CLC and CLF can account for many of the effects of CNTFRalpha on developing motoneurons.

Animals↗

PubMed2003

Neuromuscular development after the prevention of naturally occurring neuronal death by Bax deletion.

The removal of excess neurons by programmed cell death (PCD) is believed to be critical for the proper development and function of the nervous system. A major role of this neuronal loss is to attain quantitative matching of neurons with their targets and afferents. Because motoneurons (MNs) in Bax knock-out (Bax KO) mice fail to undergo PCD in the face of normal target muscle development, we asked whether the excess rescued neurons in Bax KO mice can develop normally. We observed many small atrophied MNs in postnatal Bax KO mice, and these failed to innervate limb muscle targets. When examined embryonically during the PCD period, however, these excess MNs had initiated target innervation. To examine whether a limitation in trophic factor availability is responsible for postnatal MN atrophy and loss of innervation, we applied glial cell line-derived neurotrophic factor (GDNF) to neonatal mice. GDNF injection for 7-14 d induced the regrowth and reinnervation of muscle targets by atrophic MNs in Bax KO mice and prevented the normal postnatal death of MNs in wild-type mice. These results indicate that, although initially all of the MNs, including those rescued by Bax deletion, are able to project to and innervate targets, because of limited target-derived signals required for maintaining innervation and growth, only a subpopulation can grow and retain target contacts postnatally. Although sensory neurons in the dorsal root ganglia are also rescued from PCD by Bax deletion, their subsequent development is less affected than that of MNs.

Animals↗

PubMed2003

Differential expression of the GDNF family receptors RET and GFRalpha1, 2, and 4 in subsets of motoneurons: a relationship between motoneuron birthdate and receptor expression.

Previous studies have demonstrated the expression of specific members of the glial cell line-derived neurotrophic factor (GDNF) receptor family alpha (GFRalpha) in subsets of motoneurons (MNs) in the developing mouse spinal cord. We examined the expression pattern of GFRalpha and RET in the avian lumbar spinal cord during the period of programmed cell death (PCD) of MNs by using double labeling in situ hybridization and immunohistochemistry. In the lateral motor column (LMC) of the lumbar spinal cord, a laminar organization of GFRalpha expression was observed: GFRalpha1-positive MNs were located in the medial LMC; GFRalpha1-, 2-, and 4-positive MNs were situated in the lateral LMC; and GFRalpha4-positive MNs were located in the intermediate LMC. The species of GFRalpha receptor that was expressed in MNs was found to be related to their birthdates. The expression of subpopulation-specific transcriptional factors was also used to define MNs that express a specific pattern of GFRalpha. This analysis suggests that motor pools as defined by these transcriptional factors have unique expression patterns of GFRalpha receptor. Early limb bud ablation did not affect the expression of GFRalpha in the spinal cord, indicating that regulation of receptor expression is independent of target-derived signals. Finally, GDNF mRNA expression was found in the limb during the PCD period of MNs. In conclusion, these results indicate that time of withdrawal from the mitotic cycle may specify the expression pattern of GFRalpha in subsets of MNs and that GDNF may function as a target-derived neurotrophic factor for specific subpopulations of MNs.

Animals↗

PubMed2003

Developmental expression of nicotinic receptors in the chick and human spinal cord.

Naturally occurring programmed cell death of lumbar motor neurons in the chick spinal cord occurs between embryonic day (E) 6 and E12; whereas, a peak of motor neuron degeneration in the human spinal cord occurs between 12 and 16 weeks gestation. One of the major neurotransmitters, acetylcholine, is released from the embryonic motor neuron early in development and is thought to be responsible for early muscle activity that serves as a signal for regulating motor neuron survival. The effects of acetylcholine are mediated by two functionally distinct classes of receptors; namely, muscarinic and nicotinic with nicotinic receptors being used at the neuromuscular synapse. In this study, we determined the developmental expression profile of nicotinic acetylcholine receptor subunits in the chick and human lumbar motor neurons and skeletal muscle using reverse transcription polymerase chain reaction, immunoblots, and immunocytochemistry. Our results show that, in the chick, nicotinic receptor subunits alpha1, alpha4, alpha7, alpha8, and beta2 appear to be regulated during the process of naturally occurring motor neuron cell death in the spinal cord. A new finding was the expression of alpha8 mRNA and protein from E4.5 through E7 in chick motor neurons. Interestingly, we also found that, at E14, alpha8 protein was localized only in sensory dorsal horn neurons. In the developing human spinal cord, we determined that nicotinic receptor subunits alpha1, alpha2, alpha3, alpha4, alpha7, beta2, and beta3 were expressed before the programmed cell death period, and alpha2, alpha4, alpha7, beta2, beta3, and beta4 were expressed during the programmed cell death period. Our data demonstrate that neuronal and muscle nicotinic receptor mRNAs and proteins are expressed during important embryonic periods. This finding raises the possibility that nicotinic receptors play an important role in the spinal cord and skeletal muscle during early development.

Adult↗

PubMed2003

Inhibition of caspases promotes long-term survival and reinnervation by axotomized spinal motoneurons of denervated muscle in newborn rats.

We examined whether (1) a pan-caspase inhibitor, Boc-D-FMK, exerts long-term neuroprotective effects on spinal motoneurons (MNs) after root avulsion in neonatal rats and (2) whether the rescued spinal MNs regenerate their axons into a peripheral nerve (PN) graft and reinnervate a previously denervated target muscle. Eight weeks after root avulsion, 67% of spinal MNs remained in the Boc-D-FMK-treated group, whereas all MNs died in the sham control group. By 12 weeks postinjury, however, all Boc-D-FMK treated MNs died. In the regeneration experiment, a PN graft was implanted at different times after injury. The animals were allowed to survive for 4 weeks following the operation. Without caspase inhibition, MNs did not regenerate at any time point. In animals treated with Ac-DEVD-CHO, a caspase-3-specific inhibitor, and Boc-D-FMK, 44 and 62% of MNs, respectively, were found to regenerate their axons into a PN graft implanted immediately after root avulsion. When the PN graft was implanted 2 weeks after injury, however, MNs failed to regenerate following Ac-DEVD-CHO treatment, whereas 53% of MNs regenerated their axons into the graft after treatment with Boc-D-FMK. No regeneration was observed when a PN graft was implanted later than 2 weeks after injury. In the reinnervation study, injured MNs and the target biceps muscle were reconnected by a PN bridge implanted 2 weeks after root avulsion with administration of Boc-D-FMK. Eight weeks following the operation, 39% of MNs reinnervated the biceps muscle. Morphologically normal synapses and motor endplates were reformed in the muscle fibers. Collectively, these data provide evidence that injured neonatal motoneurons can survive and reinnervate peripheral muscle targets following inhibition of caspases.

Animals↗

PubMed2003

Rescue of developing spinal motoneurons from programmed cell death by the GABA(A) agonist muscimol acts by blockade of neuromuscular activity and increased intramuscular nerve branching.

Blockade of neuromuscular activity in the chick embryo during the period of programmed cell death of motoneurons results in a complete rescue of these cells. Understanding the cellular mechanisms that mediate this counterintuitive effect is of considerable interest with respect to the regulation of motoneuron survival during development as well as for understanding why motoneurons die pathologically. Although considerable evidence supports the role of a peripheral site of action at the neuromuscular junction in mediating the rescue of motoneurons following activity blockade, some evidence also supports a role for central nervous system (CNS) neurons. For example, the rescue of motoneurons by curare has been reported to be blocked by the GABA(A) agonist muscimol via its actions on CNS neurons. We have carried out a series of studies to further investigate this interesting observation. Surprisingly, we find that: (1) muscimol blocks activity and rescues MNs in a dose-dependent manner, similar to curare; (2) muscimol's effects on MN survival appear to be mediated by its action on intramuscular nerve branching, similar to curare; and (3) although muscimol acts centrally, the effects of muscimol on MN survival and axon branching are mediated peripherally at the neuromuscular junction, similar to curare. Because muscimol reduces MN depolarization these data also suggest that the depolarization of MNs by afferents is not required for promoting MN survival. Taken together, these data provide further evidence in support of a peripheral site of action of activity blockade in rescuing motoneurons from developmental cell death.

Animals↗